Compositions for use in treatment of dermatological diseases and conditions

ABSTRACT

Compositions containing an effective dermatological disease-treating or dermatological condition-treating active agent and a pharmaceutically-acceptable carrier or vehicle are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS/INCORPORATION BY REFERENCESTATEMENT

The present application is a divisional application of U.S. Ser. No.12/751,728, filed Mar. 31, 2010; which claims benefit of InternationalPatent Application PCT/US2008/079534, filed Oct. 10, 2008, in accordancewith 35 U.S.C. §119 and §365; which claims benefit under 35 U.S.C.119(e) of U.S. Provisional Application Ser. No. 60/998,345, filed Oct.10, 2007, and U.S. Provisional Application Ser. No. 61/126,478, filedMay 5, 2008. The entirety of each of these applications is herebyexpressly incorporated herein by reference.

BACKGROUND

Human skin comprises an epidermis layer, which is predominantly composedof keratinocytes and a small number of melanocytes and Langerhans cells(antigen presenting cells), and a dermis layer, which is primarilycomposed of fibroblasts. The majority of skin disorders involveinflammation triggered by some insult to the skin. Keratinocytes respondquickly to environmental stimuli (e.g., UV radiation (UVR), allergens,irritants or physical damage) by producing a variety of inflammatorymediators, including cytokines (e.g., IL-1, TNF-alpha, and IL-6) andchemokines (e.g., IL-8). One of the most active inflammatory mediatorsis PGE-2 (Prostaglandin E2) and, of course, many topical dermatologydrugs have been designed to lower levels of PGE-2. The fibroblasts inthe dermis also produce PGE-2 along with a variety of chemokines,cytokines and matrix destroying enzymes such as collagenase (MMP-1).

The identification of compounds that can suppress the production ofinflammatory mediators in the skin would allow effective topicalproducts to be developed to treat a variety of inflammatory skindiseases or disorders including eczema, radiation dermatitis, atopicdermatitis, actinic keratosis, seborrheic dermatitis, other dermaticdiseases and acne. Compositions able to treat other dermatologicalconditions such as aging effects and hyperpigmentation would also bedesirable.

BRIEF DESCRIPTION OF THE DRAWINGS

This patent or application file contains at least one drawing executedin color. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 is a graph showing the effects of dihydroeugenol (DHE) onUV-induced PGE-2 in fibroblasts.

FIG. 2 is a graph showing the effects of DHE on UV-induced PGE-2 inkeratinocytes.

FIG. 3 is a graph showing the effects of DHE on TPA-induced TNF-α inkeratinocytes.

FIG. 4 is a graph showing the effects of DHE on LPS-induced inflammatorycytokines in monocytes.

FIG. 5 is a photograph of an arm of a human subject which was exposed toerythema-inducing UVB radiation and treated with a lotion of thepresently claimed and disclosed inventive concept(s).

FIG. 6 shows photographs of a human subject's face which has symptoms ofrosacea. Facial areas of rosacea are shown in (A) while these areas, 12weeks after initiation of treatment with DHE, IE, and cinnamaldehyde,are shown in (B).

FIG. 7 shows the effects of topical DHE application on patientsundergoing radiation treatment. (A) Radiation dermatitis in a typicalradiation patient untreated for radiation dermatitis. (B) A patient wastreated with a topical 2% DHE lotion daily during 35 radiationtreatments. The photograph was taken after the 35^(th) treatment and theskin shows no evidence of radiation dermatitis. (C) A close-upphotograph of the patient of (B), one month after the end of radiationtreatments. There is no evidence of radiation damage to the skin.

FIG. 8 is a graph showing stimulation of collagen 1 mRNA in fibroblastsby DHE, isoeugenol (IE), and Ethyl vanillin (EV).

FIG. 9 is a graph showing stimulation of elastin mRNA in fibroblasts byDHE, IE and EV.

FIG. 10 is a graph showing stimulation of hyaluronic acid synthase-2 inRNA in fibroblasts by DHE, IE and EV.

FIG. 11 is a graph showing stimulation of tissue inhibitor ofmetalloprotinease-1 mRNA (TIMP-1) in fibroblasts by DHE, IE and EV.

FIG. 12 is a graph showing inhibition of matrix metalloprotenases (MMPs)in fibroblasts by ethyl vanillin.

FIG. 13 is a graph showing inhibition of melanin synthesis in vitro byisoeugenol (referred to in the figure as TH-212).

FIG. 14 shows photographs which demonstrate the loss of pigment in humanmelanocyte cultures treated with isoeugenol (TH-212) and isoeugenolacetate (referred to in the figure as TH-213) for 9 days.

FIG. 15 shows photographs which demonstrate how a topically-appliedformulation of isoeugenol acetate (referred to in the figure as TH-212ester) plus salicylic acid causes a clearing of acne andhyperpigmentation after a 4 week treatment.

FIG. 16 shows photographs which demonstrate how a topically-appliedformulation of isoeugenol acetate (TH-212 ester) plus 2% salicylic acidremoves hyperpigmentation after a 30-day treatment period.

FIG. 17 shows photographs which demonstrate how a topically-appliedformulation of isoeugenol acetate (TH-212 ester) plus 2% salicylic acidreduces sun-induced hyperpigmentation after a 30-day treatment period.

FIG. 18 shows a photograph of cell extracts treated with isoeugenol(TH-212) and isoeugenol acetate (TH-213) then provided with L-DOPA, atyrosinase substrate. Cell lysates were prepared from human melanocytes.The amount of tyrosinase in these cell lysates was determined by DOPAoxidase assay. Results show a high level of tryosinase in Control(untreated) cell lysates, and an absence of tyrosinase activity (lack ofcolor) in assay tubes containing cell extracts obtained from melanocytestreated with TH-212 or TH-213.

FIG. 19 shows photographs which demonstrate psoriatic skin before (A)and after (B) treatment with a formulation comprising DHE and IE.

DETAILED DESCRIPTION

The description herein of several embodiments describes non-limitingexamples that further illustrate the presently claimed and disclosedinventive concept(s).

In the following detailed description, numerous specific details are setforth in order to provide a more thorough understanding of thedisclosure. However, it will be apparent to a person having ordinaryskill in the art that the presently claimed and disclosed inventiveconcept(s) may be practiced without these specific details. In otherinstances, features which are well known to persons of ordinary skill inthe art have not been described in detail to avoid complicationunnecessarily the description.

Therefore, unless defined otherwise, all technical and scientific termsused herein have the same meanings as commonly understood by one skilledin the art to which the presently claimed and disclosed inventiveconcept(s) pertains. For example, the term “plurality” refers to “two ormore.” The singular forms “a,” “an,” and “the” include plural referentsunless the context clearly indicates otherwise. The term “about”, whereused herein when referring to a measurable value such as an amount, atemporal duration, and the like, is meant to encompass variations of±20% or ±10%, more particularly ±5%, even more particularly ±1%, andstill more particularly ±0.1% from the specified value, as suchvariations are appropriate to perform the disclosed methods.

Turning now to the presently claimed and disclosed inventive concept(s),compositions are contemplated herein that comprise compounds, inparticular dihydroeugenol (DHE) and/or isoeugenol (IE) and/or ethylvanillin (EV) or salts, esters, ethers, or derivatives thereof; alsocontemplated herein are methods for topically or systemically deliveringthem for treatment against inflammation-related and other dermatologicalconditions such as described herein. These DHE and/or IE and/or EV orsalts, esters, ethers or derivatives thereof also are delivered to ameasurable extent transepidermally and/or transdermally. In one of itsmethod aspects, this presently claimed and disclosed inventiveconcept(s) is directed to a method for treating a patient with adermatological disease or condition by topically administering to saidpatient a pharmaceutical or cosmetic composition comprising apharmaceutically or cosmetically acceptable topical carrier and aneffective dermatological disease, disorder or condition-treating amountof a formulation of DHE and/or IE and/or EV, or salts, esters, ethers,or derivatives thereof. In particular, the presently claimed anddisclosed inventive concept(s) is directed to a method of using acomposition comprising one or more of DHE and/or IE and/or EV or salts,esters, ethers, or derivatives for treating dermatologic diseases,disorders or conditions, aging effects related to decreasing productionof collagen, elastin, or hyaluronic acid, or to hyperpigmentation. Theformulations may further contain cinnamaldehyde.

The presently claimed and disclosed inventive concept(s) is directed tomethods and compositions for treating a variety of skin disorders,diseases, and conditions including for example, rosacea, radiationdermatitis, erythemas (sunburns), psoriasis, atopic dermatitis, allergicand irritant contact dermatitis, actinic keratitis, acne, scarring,hyperpigmentation, and seborrheic dermatitis or eczema, or othereczemas, and alopecia greata, wherein the compounds act, for example, onskin keratinocytes and fibroblasts and on immune cells such as monocytesand on melanocytes. The presently claimed and disclosed inventiveconcept(s) further comprises methods and compositions for mitigating theeffects of aging, e.g., by enhancing production of collagen, elastin andhyaluronic acid synthases in skin fibroblast cells.

Inflammatory skin diseases are the most common problem in dermatology.They come in many forms, from occasional rashes accompanied by itchingand redness to chronic conditions such as dermatitis (eczema), rosacea,seborrheic dermatitis, and psoriasis. However, they are all linked byone common factor, inflammation. It has been found that the inflammatorymarkers (cytokines) produced by skin and immune cells that are requiredfor the development of an inflammatory response, such as atopicdermatitis and radiation dermatitis. The presently claimed and disclosedinventive concept(s) comprises agents that suppress the production of avariety of inflammatory responses in cultured skin cells (keratinocytesand fibroblasts), and immune cells (monocytes and T-lymphocytes) and inintact living skin. As a result of blocking these inflammatory processesin the skin, the present compounds are able to effectively reduce oreliminate a variety of inflammatory symptoms that occur with common skinproblems.

Rosacea is a vascular, inflammatory skin disorder that affectsapproximately 5% of the population and is characterized by frequentperiods of facial redness or flushing caused by over-active capillaries.Over time, this chronic state of skin inflammation gives rise to avariety of rosacea symptoms. Rosacea is sometimes characterizedmistakenly as adult-acne because patients present with a reddened faceand acne-like symptoms. However, individuals affected with this skindisease also may have persistent redness with accompanying pain anditching in areas such as the forehead, chin, nose, ears, chest and back.As the disease progresses, small blood vessels and tiny pimples (calledpapules or pustules) begin to appear on and around the reddened area. Insevere cases rosacea can affect the eyes (ocular rosacea) and causedisfigurement of the nose (rhynophyma). In addition to the physicalsymptoms associated with rosacea, patients also suffer significantpsychological and social problems if left untreated.

Regarding skin aging, research shows that there are, in fact, twodistinct types of skin aging. Aging caused by inherited genes is calledintrinsic (internal) aging. The other type of aging is known asextrinsic (external) aging and is caused by environmental factors, suchas exposure to the sun's rays. Intrinsic aging, also known as thenatural aging process, is a continuous process that normally begins inour mid-20s. Within the skin the dermis of normal (wrinkle-free) skin iscomposed of abundant amounts of type I collagen and type VII collagen,as well as elastin, which provides tissue strength, resiliency andrecoil. However, as the dermal fibroblasts which produce collagen andelastin begin to age, they produce decreasing amounts of these proteins.Further, aging fibroblasts produce increased amounts of enzymes calledmatrix metaloproteinases (MMP's), which degrade collagen and elastin.This results in a drastic loss of collagen and elastin over time andresults in skin laxity and fragility, visible in the form of fine linesand wrinkles. The signs of intrinsic aging are: fine wrinkles, thin andtransparent skin, loss of underlying fat, leading to hollowed cheeks andeye sockets as well as noticeable loss of firmness on the hands andneck, dry skin that may itch, graying hair that eventually turns white,and hair loss. Genes control how quickly the normal aging processunfolds. Some persons notice their first gray hairs in their 20s; othersdo not see graying until their 40s.

A number of extrinsic aging factors often act together with the normalaging process to prematurely age our skin. Most premature aging iscaused by sun exposure. Other external factors that prematurely age ourskin are repetitive facial expressions, gravity and smoking. Withoutprotection from the sun's rays, just a few minutes of exposure each dayover the years can cause noticeable changes to the skin. Freckles, agespots, spider veins on the face, rough and leathery skin, fine wrinklesthat disappear when stretched, loose skin, a blotchy complexion and skincancer can all be traced to sun exposure. “Photoaging” is the termdermatologists use to describe this type of aging caused by exposure tothe sun's rays. The amount of photoaging that develops depends on: (1) aperson's skin color and (2) his or her history of long-term or intensesun exposure. Persons with fair skin who have a history of sun exposuredevelop more signs of photoaging than those with dark skin. In thedarkest skin, the signs of photoaging are usually limited to finewrinkles and a mottled complexion.

Photoaging occurs over a period of years. With repeated exposure to thesun, the skin loses the ability to repair itself, and the damageaccumulates. Scientific studies have shown that repeated ultraviolet(UV) exposure impairs the synthesis of new collagen and increases theexpression of MMP enzymes, which break down collagen. The sun alsocauses excessive elastin production but the elastin made is abnormal andaggregates into clumps, leading to a condition referred to bydermatologists as elastosis. Due to the loss of collagen and theproduction of abnormal elastin, sun-weakened skin ceases to spring backcompared to skin protected from UV rays. Skin also becomes loose,wrinkled, and leathery much earlier with unprotected exposure tosunlight.

While there is nothing currently available to stop the aging process, itis possible to slow the rate at which the skin ages. As described above,both intrinsic and photoaging are due to the breakdown and loss ofcollagen and elastin in the skin. The present compositions containingredients that have been scientifically proven herein to increase theproduction of collagen and elastin, as well as reduce the expression ofMMP enzymes. These two effects slow the aging process and can even aidin rebuilding the dermal matrix, which reduces the appearance of new andexisting wrinkles and fine lines.

Another skin condition, acne, is the most common skin disorder seen bydoctors and affects almost everyone at some time. Teenagers are affectedmost often. Acne can cause a great deal of embarrassment and anxiety andcan even cause people to become depressed which can lead to withdrawingfrom friends, and performing poorly at school or work. The exact causeof acne is unknown, but the following factors are considered important.(1) Acne is the visible end result of hormonal, bacterial andinflammatory disturbances that take place at the level of the oil pore(pilosebaceous follicle). (2) As the process advances, greater amountsof oil may be produced within the sebaceous glands, though the change incomposition and quality of the oil may be more important than thequantity, the scale produced on the inside walls of the hair folliclebecomes stickier and it builds up and blocks the pore which shows up aswhiteheads and blackheads (comedones). (3) The acne bacteria(Propionobacterium acnes) grow and multiply in the retained oil. Thesebum acts as a nutrition source for the bacterial, which in turnrelease chemicals within the pore. These alert and attract white cellsfrom the blood leading to inflammation. (4) As these inflamed hairfollicles (pores) and glands enlarge, the surrounding skin also becomesinflamed and may lead to even larger lumps and cysts (also callednodules). (5) Inflammation may damage the cells that make collagen. Lesscollagen production causes thinning of the skin, which is seen asdepressed scars. Occasionally, collagen production will increase, whichthen causes the scars to become thickened. The present formulations mayalso be used to heal scars from acne and stretch marks by improvingtheir structure and coloration.

Another skin disorder, psoriasis, is a chronic (long-lasting) skindisease characterized by scaling and inflammation. Scaling occurs whencells in the outer layer of skin reproduce faster than normal and pileup on the skin's surface. Psoriasis affects 2 to 2.6 percent of theUnited States population, or almost 5.8 to 7 million people. It occursin all age groups and about equally in men and women. People withpsoriasis may suffer discomfort, restricted motion of joints, andemotional distress. When psoriasis develops, patches of skin thicken,redden, and become covered with silvery scales. These patches aresometimes referred to as plaques. They may itch or burn. The skin atjoints may crack. Psoriasis most often occurs on the elbows, knees,scalp, lower back, face, palms, and soles of the feet. The disease alsomay affect the fingernails, toenails, and the soft tissues inside themouth and genitalia. About 10 percent of people with psoriasis havejoint inflammation that produces symptoms of arthritis. This conditionis called psoriatic arthritis.

Research indicates that psoriasis may be a disorder of the immunesystem. The immune system includes a type of white blood cell, called aT cell, that normally helps protect the body against infection anddisease. In psoriasis, the immune system produces too many T cells, inthe skin. These T cells trigger the inflammation and excessive skin cellreproduction seen in people with psoriasis. This leads to inflammationand flaking of skin. The presently claimed and disclosed inventiveconcept(s) inhibits the production of the same inflammatory mediatorsthat other psoriasis therapies target, but since it is in topical form,it does not require frequent injections nor does it lower body's overallimmune function.

Eczema is a general term for many types of skin inflammation(dermatitis). Atopic dermatitis is the most common of the many types ofeczema. Several other forms have very similar symptoms. The diversetypes of eczema are listed and briefly described below.

(1) Atopic dermatitis is a chronic skin disease characterized by itchy,inflamed skin. The word “dermatitis” means inflammation of the skin.“Atopic” refers to diseases that are hereditary, tend to run infamilies, and often occur together. These diseases include asthma, hayfever, and atopic dermatitis. In atopic dermatitis, the skin becomesextremely itchy and inflamed, causing redness, swelling, cracking,weeping, crusting, and scaling. Atopic dermatitis most often affectsinfants and young children, but it can continue into adulthood or firstshow up later in life. In most cases, there are periods of time when thedisease is worse, called exacerbations or flares, which are followed byperiods when the skin improves or clears up entirely, called remissions.Many children with atopic dermatitis enter into a permanent remission ofthe disease when they get older, although their skin often remains dryand easily irritated. Environmental factors can activate symptoms ofatopic dermatitis at any time in the lives of individuals who haveinherited the atopic disease trait. The cause of atopic dermatitis isunknown, but the disease seems to result from a combination of geneticand environmental factors. Evidence suggests that the disease isassociated with other so-called atopic disorders such as hay fever andasthma, which many people with atopic dermatitis also have. In addition,many children who outgrow the symptoms of atopic dermatitis go on todevelop hay fever or asthma. Although one disorder does not causeanother, they may be related, thereby giving researchers clues tounderstanding atopic dermatitis. Atopic dermatitis is very common andaffects males and females equally and accounts for 10 to 20% of allreferrals to dermatologists. Atopic dermatitis occurs most often ininfants and children and its onset decreases substantially with age.Scientists estimate that 65 percent of patients develop symptoms in thefirst year of life, and 90 percent develop symptoms before the age of 5.Onset after age 30 is less common and often occurs after exposure of theskin to harsh conditions. People who live in urban areas and in climateswith low humidity seem to be at an increased risk for developing atopicdermatitis. About 10% of all infants and young children experiencesymptoms of the disease. Roughly 60 percent of these infants continue tohave one or more symptoms of atopic dermatitis even after they reachadulthood. This means that more than 15 million people in the UnitedStates have symptoms of the disease.

(2) Contact eczema is a localized reaction that includes redness,itching, and burning where the skin has come into contact with anallergen (an allergy-causing substance) or with an irritant such as anacid, a detergent (soap, bodywash), or other chemical.

(3) Allergic contact eczema is a red, itchy, weepy reaction where theskin has come into contact with a substance that the immune systemrecognizes as foreign, such as poison ivy or certain preservatives increams and lotions.

(4) Seborrheic eczema is a form of skin inflammation of unknown causebut which is associated with a certain type of yeast that lives on theskin. Seborrheic eczema presents as yellowish, oily, scaly patches ofskin on the scalp, face, and occasionally other parts of the body(called cradle cap in infants).

(5) Nummular eczema is coin-shaped patches of irritated skin—mostcommonly on the arms, back, buttocks, and lower legs—that may becrusted, scaling, and extremely itchy.

(6) Neurodermatitis is scaly patches of skin on the head, lower legs,wrists, or forearms caused by a localized itch (such as an insect bite)that becomes intensely irritated when scratched.

(7) Stasis dermatitis is a skin irritation on the lower legs, generallyrelated to circulatory problems.

(8) Dyshidrotic eczema is irritation of the skin on the palms of handsand soles of the feet characterized by clear, deep blisters that itchand burn.

Radiation therapy, another skin disorder, can have some unpleasant sideeffects in the skin. The following are the most common side effects,both acute and chronic, resulting from radiation. Unforeseen sideeffects may occur because of the unique and varied tolerance ofindividual persons. Late effects of treatment may not always bepredictable and may be influenced by concurrent and/or subsequenttreatment for this and other diseases.

Specific side effects of radiotherapy depend on the part of the bodybeing treated as well as the dose given. In general, the first change isa reddening of the skin, resembling a sunburn. In many patients this isall that is experienced. However, in most patients the burn can besevere and in many cases equivalent to second degree burns. Like asunburn, the involved area is often sensitive and even painful to thetouch. In addition, the overlying skin may break down and the area mayremain open until several days to weeks after the course of radiation iscompleted. Once the course of radiotherapy is completed, the rednesswill gradually go away and any open areas normally will heal. However,the skin in this area will most likely develop features of aged skinincluding pronounced wrinkling, skin thinning, stiffness and/or dryness,as well as possible pigmentation changes.

Most of the current treatment options for radiation dermatitis involvethe use of emollients or aloe gels in an attempt to keep the skinmoisturized. However, as most know who have had the experience of asunburn, moisturization helps the skin from drying out but does notreduce the pain or redness, which are caused by inflammation. Thepresently claimed and disclosed inventive concept(s) comprises amoisturizing lotion that contains an active agent, a bioactive that isable to reduce skin redness and pain associated with radiation therapy.

Another skin disorder, hyperpigmentation, is a common and distressingcondition afflicting a large subset of the population. Hyperpigmentationis the result of an increased amount of melanin in the epidermis, thedermis, or both. This pigmentary change can be divided into 2pathophysiologic processes: melanocytosis (increased number ofmelanocytes) and melanosis (increased amount of melanin).

In a particular embodiment, the presently claimed and disclosedinventive concept(s) comprises a formulation comprising dihydroeugenol.The DHE formulation may be administered topically, systemically, ororally administered to a subject having rosacea for example for treatingand reducing the rosacea on the subject's skin. The DHE formulation mayalso be used for example to treat and/or inhibit psoriasis and radiationdermatitis in a subject. The formulation may comprise, with or insteadof the DHE, a salt, ester, or ether, thereof as described elsewhereherein. The formulation may further comprise one or more of isoeugenol(IE) or of a salt, ester, or ether thereof, for example isoeugenylacetate or methyl isoeugenol. Any of these formulations may also be usedto treat inflammatory skin conditions such as actinic keratitis, acne,scarring, allergic and irritant contact dermatitis, atopic dermatitis,erythema (sunburn), hand eczema, seborrheic dermatitis, alopecia greata,and other inflammatory irritations of the skin. Formulations comprisingisoeugenol and salts, esters, and ethers thereof can be used inparticular to reduce the effects of hyperpigmentation of the skin.

In particular embodiments, the compositions of the presently claimed anddisclosed inventive concept(s) comprise synthetic and/or naturalversions of the compounds dihydroeugenol (DHE) and/or isoeugenol (IE)and/or ethyl vanillin (EV), and/or salts, esters, ethers or derivativesof DHE, IE and EV, or combinations thereof and particularly salts,esters, ethers, and derivatives of DHE, IE and EV including isoeugenolacetate, for example.

In one of its compositional aspects, this presently claimed anddisclosed inventive concept(s) is directed to pharmaceuticalcompositions for topical, transdermal or other systemic administrationcontaining a pharmaceutically-acceptable carrier and DHE and/or IEand/or EV and/or salts, esters, ethers or derivatives thereof orcombinations thereof as described herein. In particular, the presentlyclaimed and disclosed inventive concept(s) is directed to a compositioncomprising DHE and/or IE and/or EV and/or salts, esters, ethers orderivatives thereof or combinations thereof for use in treatingdermatologic diseases, disorders or conditions.

In one of its method aspects, this presently claimed and disclosedinventive concept(s) is directed to a method for treating a patient witha dermatological disease, disorder, or condition by topicallyadministering to said patient a pharmaceutical composition comprising apharmaceutically acceptable topical carrier and an effectivedermatological disease-treating or condition-treating amount of aformulation of DHE and/or IE and/or EV and/or salts, esters, ethers, orderivatives thereof or combinations thereof.

In another one of its method aspects, this presently claimed anddisclosed inventive concept(s) is directed to a method for treating adermatological condition, in particular radiation dermatitis, bytopically applying to a human a cosmetic composition comprising apharmaceutically acceptable topical carrier and an effective amount of aformulation of DHE and/or IE and/or EV and/or salts, esters, ethers orderivatives thereof or combinations thereof. In still another of itsmethod aspects, this presently claimed and disclosed inventiveconcept(s) is directed to a method for treating a patient with aninflammatory disease, disorder, or condition by systemicallyadministering to said patient a pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective inflammatorydisease-treating amount of a formulation of DHE and/or IE and/or EVand/or salts, esters, ethers, or derivatives thereof or combinationsthereof.

In yet another of its method aspects, this presently claimed anddisclosed inventive concept(s) is directed to a method for treating ahuman with an inflammatory disease, disorder or condition by topicallyapplying to said human a pharmaceutical composition comprising apharmaceutically acceptable carrier and an effective amount of aformulation of DHE and/or IE and/or EV and/or salts, esters, ethers orderivatives thereof or combinations thereof.

In yet another of its method aspects, this presently claimed anddisclosed inventive concept(s) is directed to a method for improving theskin appearance of a person such as reducing skin aging by topicallyadministering to said person a pharmaceutical or cosmetic compositioncomprising a pharmaceutically acceptable carrier and a pharmaceuticallyor cosmetically effective amount of a formulation of DHE and/or IEand/or EV and/or salts, esters, ethers, or derivatives thereof orcombinations thereof.

In another one of its method aspects, this presently claimed anddisclosed inventive concept(s) is directed to a method for reducingareas of hyperpigmentation on the skin by topically applying to saidperson's skin a pharmaceutical or cosmetic composition comprising apharmaceutically or cosmetically acceptable carrier and an effectiveamount of a formulation of IE and/or salts, esters, ethers, orderivatives thereof (e.g., isoeugenol acetate) or combinations thereof.

An optional component of any of the formulations of the presentlyclaimed and disclosed inventive concept(s) is cinnamaldehyde.Cinnamaldehyde may be present in any of the formulations, for examplebut not by way of limitation, at a concentration in the range of 0.01%to 5%. In particular, cinnamaldehyde may be included in the presentformulations for use in treatment of rosacea, acne, and seborrheicdermatitis. The cinnamaldehyde provides both anti-inflammatory andanti-bacterial/anti-microbial effects against, for example, bacteriawhich contribute to acne and yeasts which contribute to seborrheicdermatitis.

DEFINITIONS

When describing the cosmetic and pharmaceutical compositions and methodsof this presently claimed and disclosed inventive concept(s) as well asthe compositions and methods themselves, the following terms have thefollowing meanings:

“Ionizing radiation” refers to any radiation that ionizes the atoms ormolecules of matter. It may consist of particles (such as electrons) orit may be electromagnetic (ultraviolet radiation; X-rays; gammaradiation). Ionizing radiation occurs naturally, for example as acomponent of sunlight, and is emitted by radioactive substances. It isalso produced artificially in X-ray machines, particle accelerators, andnuclear reactors, for example.

“Isolated”, when used to define the state of purity of the synthetic ornatural compounds used in the practice of this presently claimed anddisclosed inventive concept(s), means that the compounds describedherein and/or salts, esters, ethers, or derivatives thereof orcombinations thereof has been substantially freed of (i.e. at leastabout 90% and especially at least about 95%) or separated from relatedfeedstocks, raw materials, co-products, or in the case ofnaturally-occurring mixtures, related materials with which the compoundappears in nature.

“Pharmaceutically-acceptable topical carrier” and equivalent terms referto an inactive liquid or cream vehicle capable of suspending ordissolving the compounds described herein and/or salts, esters, ethers,or derivatives thereof or combinations thereof and having the propertiesof being generally nontoxic and noninflammatory when applied to theskin. This term is specifically intended to encompass carrier materialsapproved for use in topical cosmetics and topical and systemicpharmaceuticals. Representative carriers include water, silicone fluids,oils, both vegetable and mineral, cream bases, lotion bases, ointmentbases and the like. These bases include suspending agents, thickeners,penetration enhancers, and the like. Their formulation is well known tothose in the art of cosmetics and topical pharmaceuticals. Additionalinformation concerning carriers can be found in Remington'sPharmaceutical Sciences, 20th edition, 2000, Lippincott, Williams andWilkins, which is hereby expressly incorporated herein by reference inits entirety.

“Therapeutically effective dose” means a dose of a composition of thispresently claimed and disclosed inventive concept(s) which, when appliedtopically to the skin of a patient afflicted with a dermatologic orother cosmetic or medical disease, disorder, or condition, or whenadministered by another route such as systemically results in anobservable improvement in the patient's condition.

“Topical”, when used to define a mode of administration, means that amaterial is administered by being applied to the skin or to an internalepithelial layer such as within the rectum, or colon, or nasal orrespiratory passage.

“Topically effective” means that a material, when applied to the skin orepithelial layer described above, produces a desired pharmacologicalresult either locally at the place of application or systemically as aresult of transdermal passage of an active ingredient in the material.

Where used herein, the term “oil-in-water formulation” refers to aformulation wherein a continuous water phase surrounds droplets of oilor lipid in an emulsion.

Where used herein, the term “water-in-oil formulation” refers to aformulation wherein a continuous lipid or oil phase surrounds dropletsof water in an emulsion.

Where used herein the term “non-aqueous formulation” refers to aformulation having less than 1%, and particularly less than 0.1%, byweight of water in the formulation. The term “non-aqueous” is alsointended to include formulations having a negligible amount of water dueto absorption of atmospheric moisture.

Where used herein the term “emulsifier” refers to a compound which isused to promote and maintain a stable mixture or dispersion (emulsion)of oil droplets in a water phase, or water droplets in an oil phase.

Emulsifiers are, essentially, surfactants. These surfactants can beionic (cationic or anionic) or non-ionic, and they can be used alone orin combination. Emulsifiers contemplated for use herein include, but arenot limited to, cetearyl alcohol and sodium cetearyl sulfate, PEG-1000monocetyl ether, glycol stearate, glyceryl stearate, cetyl alcohol,PEG-100 stearate, ceteareth-20, or quaternary ammonium salts such asalkyl trimethyl ammonium bromide, the polyol ester glycerolmonostearate, potassium stearate, sodium lauryl sulfate, and ethoxylatedfatty alcohols. Fatty acids like stearic acids may be included toregulate the consistency of the emulsion. Finally, polymers such ascarbomers can be included in small amounts to stabilize the emulsion.

Penetration enhancers are substances which enhance passage oftopically-applied compounds into the stratum, corneum of the skin andtherefrom into the epidermis and dermis. Examples include, but are notlimited to: dimethylisosorbide, ethoxydiglycol,1-dodecylazacycloheptan-2-one, propylene glycol, oleyl alcohol,polyoxyethylene ester, sorbitan mono-9-octadecenoate,poly(oxy-1,2-ethanediyl) and derivatives thereof, ethanol, glycerylmonoethyl ether, monoglycerides, isopropylmyristate, lauryl alcohol,lauric acid, lauryl lactate, terpinol, menthol, D-limonene,beta-cyclodextrin, DMSO (dimethyl sulfoxide), polysorbates, fatty acids(e.g., oleic), bile salts, N-methylpyrrolidone, polyglycosylatedglycerides, 1-dodecylazacycloheptan-2-one (Azone®),Cyclopentadecalactone (CPE-215®), Alkyl-2-(N,N-disubstitutedamino)-alkanoate ester (NexAct®), 2-(n-nonyl)-1,3-dioxolane (DEPA®), andpenetration enhancers shown for example in U.S. Pat. Nos. 3,909,816;4,405,616; 4,801,586; 4,861,764; 4,886,783; 4,983,396; 5,118,845; and5,196,410, each of which is hereby expressly incorporated herein byreference in its entirety.

Where the compositions and methods of the presently claimed anddisclosed inventive concept(s) comprise isoeugenol or dihydroeugenol,the presently claimed and disclosed inventive concept(s) in particularcontemplates methods of inhibiting or treating dermatologicalconditions, disorders, or diseases by epithelial application ofcompositions comprising esters and ethers of isoeugenol anddihydroeugenol, including, but not limited to, isoeugenyl formate,isoeugenyl acetate, isoeugenyl propionate, isoeugenyl butyrate,isoeugenyl isobutyrate, isoeugenyl oleate (and other unsaturated fattyacid esters), isoeugenyl benzoate, isoeugenyl phthalate, isoeugenylhexanoate, isoeugenyl heptanoate, isoeugenyl octanoate, isoeugenylpentanoate, isoeugenyl decanoate, isoeugenyl lactate, isoeugenylcinnamate, isoeugenyl valerate, isoeugenyl isovalerate, isoeugenylnonanoate, isoeugenyl caprylate, isoeugenyl phenylacetate, isoeugenylanthranilate, isoeugenyl salicylate, isoeugenyl methyl ether (methylisoeugenol), benzyl isoeugenyl ether, isoeugenyl ethyl ether (ethylisoeugenol), and dihydroeugenyl formate, dihydroeugenyl acetate,dihydroeugenyl propionate, dihydroeugenyl butyrate, dihydroeugenyldihydrobutyrate, dihydroeugenyl oleate (and other unsaturated fatty acidesters), dihydroeugenyl benzoate, dihydroeugenyl phthalate,dihydroeugenyl hexanoate, dihydroeugenyl heptanoate, dihydroeugenyloctanoate, dihydroeugenyl pentanoate, dihydroeugenyl decanoate,dihydroeugenyl lactate, dihydroeugenyl cinnamate, dihydroeugenylvalerate, dihydroeugenyl isovalerate, dihydroeugenyl nonanoate,dihydroeugenyl caprylate, dihydroeugenyl phenylacetate, dihydroeugenylanthranilate, dihydroeugenyl salicylate, dihydroeugenyl methyl ether(methyl dihydroeugenol), benzyl dihydroeugenyl ether and dihydroeugenylethyl ether (ethyl dihydroeugenol). These esters and ethers ofisoeugenol and dihydroeugenol can be combined with various carriers,vehicles, diluents, and excipients to form topical formulations asdescribed elsewhere herein.

EXPERIMENTAL EXAMPLES

While the presently claimed and disclosed inventive concept(s) will nowbe described herein in connection with certain examples and embodimentsso that aspects thereof may be more fully understood and appreciated, itis not intended that the presently claimed and disclosed inventiveconcept(s) be limited to these particular embodiments or examples. Onthe contrary, it is intended that all alternatives, modifications andequivalents are included within the scope of the presently claimed anddisclosed inventive concept(s) as defined by the appended claims. Thusthe examples described herein, which include particular embodiments,will serve to illustrate the practice of this presently claimed anddisclosed inventive concept(s), it being understood that the particularsshown are by way of example and for purposes of illustrative discussionof particular embodiments of the presently claimed and disclosedinventive concept(s) only and are presented in the cause of providingwhat is believed to be the most useful and readily understooddescription of procedures as well as of the principles and conceptualaspects of the presently claimed and disclosed inventive concept(s).

Example 1

In one study, various concentrations of DHE were added to culture mediumand these media were placed on human fibroblast cell cultures (resultsshown in FIG. 1). Cells were either not induced or induced with UVBradiation to stimulate cytokine/PGE-2 production. At 24 hours aftertreatment, the cell culture medium was removed and assayed by ELISAmethods for the expression of PGE-2, various cytokines and chemokines.

As is shown in FIG. 1, UV radiation (UVR) treatment of fibroblastsresults in a 6 fold increase in PGE-2. When DHE at a concentration aslow as 10 micromolar was put into the culture media after irradiation,it completely blocked the UVR induction of PGE-2.

When similar experiments were carried out with human keratinocytes, DHEwas again found to markedly suppress the UVR induction of PGE-2, with aconcentration of 50 uM inhibiting the production of PGE-2 by over 60%(results shown in FIG. 2). Since PGE-2 is the major inflammatorymediator responsible for sunburn these data indicate the efficacy of DHEin the treatment of sunburn. Further, since PGE-2 is known to be aprincipal factor in the development of actinic keratosis and skincancer, DHE can also be used in treating these conditions.

Inflammatory mediators produced in the skin contribute to thedevelopment and propagation of such diseases as rosacea, psoriasis andatopic dermatitis. While many inflammatory mediators are involved inthese diseases, TNF-α is known to be a major cytokine involved inpsoriasis. For atopic dermatitis, TNF-α, IL-8, and MCP-1 are importantmediators of inflammation in these diseases. DHE is effective insuppressing the TPA-induced (TPA is tetradecanolyl phorbol ester)production of TNF-α by approximately 50% at a 100 micromolarconcentration (results shown in FIG. 3).

In monocytes (as shown in FIG. 4), dihydroeugenol can inhibit theproduction of the cytokine TNF-α as well as the chemokines, IL-8, andMCP-1 (monocyte chemotactic protein 1). Since these inflammatorymediators are critically important for the development of immune driveninflammatory diseases such as atopic dermatitis and psoriasis, theresults indicate that DHE can be use to treat these diseases.

A summary of some of the inflammatory mediators blocked inkeratinocytes, fibroblasts and monocytes is shown below in Tables 1, 2and 3.

Table 1 shows the inhibitory effects of DHE and IE on production ofseveral inflammatory mediators (PGE-2, IL-6, IL-8, and TNF-α) induced inkeratinocytes by exposure to TPA and UV light. DHE and IE both haveinhibitory effects on production of the inflammatory mediators inkeratinocytes.

TABLE 1 Percent Inhibition Of Inflammatory Mediators of Keratinocytes byDHE and IE Active Compounds DHE IE Concentration 100 uM 100 uMKeratinocytes (TPA) PGE2 77% 82% IL-6 30% 94% IL-8 45% 75% TNF-α 12% 71%Keratinocytes (UV) PGE2 68% 76% IL-6 30% 93% IL-8 40% 76% TNF-α 31% 60%

Table 2 shows the inhibitory effects of DHE and IE on production ofseveral inflammatory mediators (PGE-2, IL-6, and IL-8) induced infibroblasts by exposure to IL-1 and UV light. DHE and IE both haveinhibitory effects on the production of the inflammatory mediators infibroblasts.

TABLE 2 Percent Inhibition Of Inflammatory Mediators of Fibroblasts ByDHE and IE Active Compounds DHE IE Concentration 100 uM 100 uMFibroblasts (IL-1) PGE-2 86% 81% IL-6 47% 53% IL-8 46% 98% Fibroblasts(UV) PGE-2 67% 77% IL-6 49% 39% IL-8 11% 2%

Table 3 shows the inhibitory effects of DHE and IE on production ofseveral inflammatory mediators (MCP-1 (monocyte chemotactic protein-1),IL-12, TNF-α, and IL-8) induced in monocytes by LPS (lipopolysaccharide)and TNF-α. DHE and IE both have inhibitory effects on the production ofthe inflammatory mediators in monocytes.

TABLE 3 Percent Inhibition Of Inflammatory Mediators of Monocytes By DHEand IE Active Compounds DHE IE Concentration 100 uM 100 uM Monocytes(LPS) MCP-1 60% 87% IL-12 66% 80% TNF-α 78% 80% IL-8 70% 75% Monocytes(TNF-α) MCP-1 46% 82% IL-8 72% 78% IL-12 98% 100% 

Example 2

In one human clinical efficacy study the forearm of a clinical subjectwas irradiated at two sites with a dose of UVB radiation sufficient toinduce erythema (FIG. 5). Immediately after the irradiation dose, butnot before, one irradiated site was treated with a topical lotioncontaining 2% by weight of DHE while the other irradiated site wastreated with the same topical formulation without DHE (vehicle control).After 4 hours, pronounced erythema was visible at the site treated withthe vehicle control while the site treated with 2% DHE lotion displayedonly minimal erythema. This result was unexpected because strongeranti-inflammatory compounds, such as steroids, when used typically areunable to prevent UVB irradiation-induced erythema even though they aremore effective than DHE in blocking inflammatory mediators, includingPGE-2, in vitro. Therefore, the actual mechanism of action of DHE inreducing UVB radiation induced erythema likely involves more than justinhibiting inflammatory cytokines and hormones such as PGE-2. Theformulations of the presently claimed and disclosed inventive concept(s)not only are able to prevent induction of erythema but are also able toreverse erythema that is pre-existing.

Example 3

In addition to its ability to block radiation induced erythema (as shownin Example 2) another unexpected finding is that topically-applied DHEis effective in reducing the symptoms of rosacea, a disease whoseetiology is for the most part not understood. Typical treatments forrosacea include topical metronidazole which is an antibiotic effectiveagainst bacteria and some parasites, and oral antibiotics. When topicalDHE and/or a combination of DHE, IE, and cinnamaldehyde was topicallyapplied, over 8-12 weeks, to patients suffering from rosacea, theresults revealed an overall improvement in their condition with use of aDHE formulation versus the same lotion base without the DHE orDHE/IE/cinnamaldehyde. The results of this study are shown in FIG. 6A-B.

Example 4

A clinical study carried out with cancer patients undergoing radiationtherapy showed that topically-applied 2% DHE lotion (applied twicedaily) can almost completely prevent the onset of radiation dermatitis.For example in a patient who underwent 35 radiation treatments forbreast cancer and who was treated with a 2% DHE lotion (e.g.,Formulation 5 shown below) daily during the 35 radiation treatments,there was no radiation damage after the 35 days of treatment or onemonth after the end of radiation treatment (see FIG. 7A-C).

Example 5

The presently claimed and disclosed inventive concept(s) furthercontemplates use of various DHE, IE and EV compositions and salts,esters, ethers, and derivatives thereof to mitigate the effects of agingon the skin. For all aging studies, normal human fibroblast cellcultures were used. These cells normally produce collagen, elastin andhyaluronic acid. As the skin ages, the fibroblasts in the dermis losetheir ability to produce these three key components of skin, and theskin consequently loses elasticity, thickness and smooth texture. Inaddition, as fibroblasts age, they increase the expression of certainenzymes that destroy collagen and elastin. There are about 13 of theseenzymes, collectively referred to as MMPs (matrix metalloproteinases).One of the principal MMPs, MMP-1, is responsible for collagendegradation. For experiments herein to determine the effects of DHE, IEand EV on collagen, elastin and hyaluronic acid, fibroblasts weretreated with the compounds for 72 hours, mRNA was then isolated, andanalyzed for abundance by RT-PCR (Reverse transcriptase—Polymerase ChainReaction). IE, DHE and EV were shown to stimulate collagen production infibroblasts.

Fibroblast cell cultures were treated with either IE, DHE or EV for 72hours at which time the amount of collagen mRNA present in the cells wasdetermined. DHE, IE and EV each caused stimulation of collagenproduction in fibroblasts, as indicated by increased collagen mRNAproduction (FIG. 8).

In addition to stimulating collagen mRNA synthesis and collagen proteinsynthesis, DHE, IE and EV and salts, esters, ethers, and derivativesthereof can increase the level of elastin mRNA in human dermalfibroblasts as shown in FIG. 9. The image is from an electrophoresis gelof DNA amplified by PCR from fibroblast mRNA. This gel was analyzed andthe density of each band quantified by image analysis software. The bargraph showing the densitometric analysis is shown above the image. DHE,IE and EV increase elastin levels in human dermal fibroblasts.

DHE, IE and EV, are also shown herein to stimulate mRNA for HAS-2. HAS-2(Hyaluronic acid synthase-2) is the enzyme that manufactures hyaluronicacid (HA) in the skin. HA is a glycosaminoglycan important formaintaining moisture and suppleness in the skin. HA has a half-life of24 hours and thus, must be continually replaced. As the skin ages, theproduction of HA decreases and this causes the skin to sag and becomethin. It has been discovered herein that DHE, either alone or incombination with EV, can also stimulate the HAS-2 gene, as shown in FIG.10. In addition EV alone can stimulate HAS-2, but the combination of DHEand salts and esters thereof and EV synergistically works better thaneither one alone.

It has also been shown herein that TIMP production can be upregulated byDHE, IE and EV. Fibroblasts in the skin not only produce enzymes (MMPs)that destroy the skin matrix but they also produce proteins (TissueInhibitors of Metalloproteinases, i.e., TIMPS) that inhibit theseenzymes. There are several TIMPs, but one that is most important forinhibiting MMPs is TIMP-1. It has been discovered that DHE, IE and EV(and salts, esters, ethers, and derivatives thereof), either alone or incombination, can significantly stimulate the production of TIMP-1,thereby providing the skin with protection against the matrix destroyingactivity of collagenase (MMP-1), the enzyme that TIMP-1 inhibits. Shownin FIG. 11 is PCR data showing the up-regulation of TIMP-1 mRNA by thesecompounds.

This Example also demonstrated inhibition of MMPs by EV. As mentionedabove, as fibroblasts age, they increase their production of MMP enzymesthat destroy collagen and elastin, particularly collagenase, MMP-1. Aprotein array blotting technique was utilized to determine the effect ofDHE, IE and EV on the protein abundance of these enzymes. As shownbelow, EV is able to reduce the level of several MMPs in human dermalfibroblasts, including MMP-1, MMP-3, MMP-8, MMP-9 MMP-10 and MMP-13(FIG. 12). This remarkable effect makes this compound an ideal additionto an anti-aging product since MMP levels in aging skin are quite high.

Example 6 IE Inhibits Melanin Synthesis

IE has been found to have a surprising and unexpected effect on blockingthe synthesis of melanin catalyzed by tyrosinase. Two ml of a sodiumphosphate buffer, pH 6.8 containing 0.2% L-DOPA(dihydroxyphenylalanine—a tyrosinase substrate) were placed in each oftwo test tubes. To one test tube was added 20 microliters of ethanol andto the other tube was added 20 microliters of a 1M stock of IE made upin ethanol (labeled TH-212). To start melanin synthesis from the L-DOPAsubstrate, 20 microliters of a tyrosinase preparation (0.5 mg/ml) wasadded to both tubes, the tubes were mixed and left at room temperature.The photograph in FIG. 13 was taken 2 hours after the start of thereaction. As can be seen in FIG. 13, melanin synthesis was almostcompletely blocked in the tube containing IE.

Without wishing to be bound by theory, it does not appear that IE isdirectly inhibiting tyrosinase, but rather is interfering with thepost-tyrosinase steps required for melanin synthesis. IE does not appearto interfere with the tyrosinase mediated conversion of DOPA todopaquinone or dopaquinone to dopachrome since the assay tube containingtyrosinase, DOPA and IE temporarily turns reddish. Since dopachrome isred, this indicates that IE is allowing tyrosinase to convert DOPA todopaquinone. The conversion of dopaquinone to dopachrome is spontaneousand does not require tyrosinase. Isoeugenol may be converting dopachrometo some chemical entity that cannot proceed down the melanin synthesispathway but remains as a colorless intermediate. Alternatively, IE mayallow dopachrome to be converted to 5,6 dihydroxyindole, the nextintermediate in the melanin pathway. It may then prevent thepolymerization of 5,6 dihydroxyindole (a colorless intermediate) tomelanin.

FIGS. 14-17 show the skin-lightening effects of topically-appliedformulations of isoeugenol and its ester isoeugenol acetate (a.k.a.isoeugenyl acetate) in the treatment of hyperpigmented areas in theskin, wherein a reduction of melanin pigment in the skin is caused bythe topical application of the formulations. In addition to blocking apost-tyrosinase step in melanin synthesis, IE and IE acetate can inhibitthe expression of the tyrosinase protein in human melanocytes. Thisinhibitory effect can be demonstrated by preparing cell extracts frommelanocytes treated for 9 days with either IE or IE-acetate or leftuntreated. If the cell extracts contain tyrosinase when an aliquot ofextract is placed in a tube containing L-DOPA (a tyrosinase substrate)in buffer, the enzyme will convert the DOPA to melanin. The melanin willappear brownish-black in the assay tube. If IE or IE-acetate hasinhibited tyrosinase synthesis in melanocytes, then the extracts fromthese cells will contain no enzyme and will not be able to producemelanin from DOPA in the assay tube. As shown in FIG. 18 very littlemelanin was made in assay tubes that contained DOPA plus cell extractsfrom either IE or IE-acetate treated cells. An inhibitory effect of IEor IE-acetate on tyrosinase synthesis can also be demonstrated by theuse of western immunoblots. In this assay, cell extracts from humanmelanocytes either left untreated or treated with 200 micromolar ofeither IE or isoeugenol acetate for 9 days are run on SDS polyacyrlamideelectrophoresis gels to separate tyrosinase from other proteins. Thetyrosinase in the gel is then blotted to a membrane and the tyrosinasedetected by staining with a specific anti-tyrosinase antibody. Theantibody-bound tyrosinase is then visualized by chemiluminescence. Theresults show that while untreated melanocytes have a high abundance oftyrosinase, the melanocytes treated for 9 days with either IE orisoeugenol acetate had almost no detectable tyrosinase present. Thisindicates that these compounds suppress the synthesis of the enzyme inhuman melanocytes.

Western immunoblots of tyrosinase abundance in human melanocyte extractstreated for 9 days with isoeugenol or isoeugenol acetate showed aconsiderable reduction in tyrosinase (as measured by RDU-relativedensitometric units). The control showed approximately 7.25 RDU, while200 μM concentrations of isoeugenol and isoeugenol acetate resulted inabout 3 RDU and 3.75 RDU, respectively (data not shown).

Regardless of the mechanism by which IE or IE acetate or other compoundsdescribed herein have their effect, the inhibition of melanin productionis essentially permanently blocked since test tubes containing DOPA, IEand tyrosinase fail to darken even after 2 weeks. The presently claimedand disclosed inventive concept(s) thus further contemplates topicallyapplying an IE composition which has a skin-penetrating vehicle toreduce or prevent the formation of melanin in vivo in keratinocytes,thereby acting as a skin lightening agent.

The presently claimed and disclosed inventive concept(s) in particularcontemplates methods of inhibiting skin pigmentation (hyperpigmentation)and causing skin lightening by topical application of compositionscomprising isoeugenol and salts, esters, and ethers of isoeugenol,including, but not limited to, isoeugenyl formate, isoeugenyl acetate,isoeugenyl propionate, isoeugenyl butyrate, isoeugenyl isobutyrate,isoeugenyl oleate (and other unsaturated fatty acid esters), isoeugenylbenzoate, isoeugenyl phthalate, isoeugenyl hexanoate, isoeugenylheptanoate, isoeugenyl octanoate, isoeugenyl pentanoate, isoeugenyldecanoate, isoeugenyl lactate, isoeugenyl cinnamate, isoeugenylvalerate, isoeugenyl isovalerate, isoeugenyl nonanoate, isoeugenylcaprylate, isoeugenyl phenylacetate, isoeugenyl anthranilate, isoeugenylsalicylate, isoeugenyl methyl ether (methyl isoeugenol), isoeugenylethyl ether (ethyl isoeugenol) and benzyl isoeugenyl ether. These estersand ethers of isoeugenol can be combined with various carriers,vehicles, diluents, and excipients to form topical formulations asdescribed elsewhere herein.

Example 7 Treatment of Psoriasis

The IE and DHE compositions (and salts, esters and ethers thereof)contemplated herein can be used to treat the scaly patches which occurin the skin of sufferers of psoriasis. Clinical treatments have shownsignificant reduction of scaling and inflammation after a 30-day courseof treatment using the compositions of Examples 4-7. For example, FIG.19 shows before (A) and after (B) pictures of a single psoriatic skinlesion after a 30 day treatment with the formulation of the presentlyclaimed and disclosed inventive concept(s) comprising DHE and IE.

Example 8 Effect of Water on Stability of EV

In a particular embodiment, the presently claimed and disclosedinventive concept(s) comprises a non-aqueous formulation of ethylvanillin, particularly comprising a silicone as the primary component(e.g., for example in the range of 20%-90% silicone). The non-aqueousformulation of ethyl vanillin can be topically applied to the skin tostimulate fibroblast production of collagen, elastin, and TIMPs in thedermis and to reduce production of MMPs in the dermis, therebyinhibiting and counteracting the effects of aging of the skin andcausing improved appearance thereof. In a certain embodiment, theformulation comprises 0.1 to 5% of ethyl vanillin. The formulation mayfurther be used to “re-model” scars in the skin wherein scars in theskin (including stretch marks and scarring due to acne) are treated soas to cause them to “disappear” i.e., to regain normal skin colorationand texture. The formulation may further comprise DHE, IE, and/or salts,esters, and/or ethers thereof and cinnamaldehyde.

In a novel discovery of the presently claimed and disclosed inventiveconcept(s), it has been found that EV cannot be placed in a water-oilemulsion without the EV significantly decomposing within 24-48 hours.This surprising and unexpected finding meant that it was necessary toidentify a carrier/vehicle system that would accommodate EV in a solubleform and at the same time maintain its chemical stability (definedherein as at least 95% of the ethyl vanillin remaining chemically intactfor at least 3 months). In one formulation contemplated herein, EV isdissolved in caprylic/capric triglyceride or other fatty acidtriglyceride and then mixed into a silicone fluid wherein the siliconeis the primary (greatest percentage) component of the formulation. Thecosmetic silicone fluid used in this embodiment accepts thecaprylic/capric triglyceride and allows the EV to remain in solution.Because the formulation contains no water (or a negligible amount, suchas less than 0.5%, due to absorption of atmospheric moisture) and noemulsifiers, the EV remains stable. Therefore, the presently claimed anddisclosed inventive concept(s) contemplates formulations of EV innon-aqueous solutions, particularly comprising at least 20% to 25% to30% to 35% to 40% to 45% to 50%, or up to 60%, 70%, 80% or 90% siliconethereby explicitly excluding water-in-oil, or oil-in-water, emulsions.Additionally, besides caprylic capric triglyceride, EV can besolubilized in jojoba oil, sunflower oil or squalane or any othersolubilizer which is accepted by the silicones.

For example, a water-in-oil formulation in which EV decomposes within 24hours (and thus is not a formulation of the presently claimed anddisclosed inventive concept(s)) is:

-   -   water (62.8%), butanediol (5%), glycerin (4%), ethoxydiglycol        (3%), glycereth-7 (2%), polysorbate 20 (0.2%), glyceryl stearate        (and) PEG-100 stearate (4%), isocetyl stearate (3.5%), jojoba        oil (3.5%), mineral oil (3%), isostearyl palmitate (3%), PEG-7        glyceryl cocoate (2%), isocetyl alcohol (2%), cetyl ricinoleate        (1%), ethyl vanillin (1%).

Pharmaceutical and Cosmetic Compositions

In certain embodiments, the DHE and/or IE and/or EV compositions, and/orsalts, esters, ethers, or derivatives thereof described herein areadministered in the form of pharmaceutical or cosmetic compositions.Such compositions can be prepared in a manner well known to those ofordinary skill in the pharmaceutical and cosmetic arts. As noted above,the compositions may further comprise cinnamaldehyde.

Generally, the compositions of this presently claimed and disclosedinventive concept(s) are administered in a cosmetic amount or atherapeutically or cosmetically effective dose. The amount of thecompound actually administered in a therapeutic setting may, typicallybe determined by a physician, such as a dermatologist in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like. In cosmetic settings, the amount to beapplied is selected to achieve a desired cosmetic effect.

The cosmetic compositions of this presently claimed and disclosedinventive concept(s) are to be administered topically (or via otherepithelial administration, where desired). The pharmaceuticalcompositions of this presently claimed and disclosed inventiveconcept(s) are to be administered topically, transdermally orsystemically such as orally or by injection or other suitable methodsknown by those of ordinary skill in the art.

In such compositions, the DHE and/or IE and/or EV and/or salts, esters,ethers, or derivatives thereof is usually a minor component (orcomponents) (from about 0.001 to about 20% by weight, or particularlyfrom about 0.01 to about 10% or 0.1% to 5%, or 1.0% to 3%, by weight),with the remainder being various vehicles or carriers and processingaids helpful for forming the desired dosing form and for carrying theactive agent into the epidermis. Cinnamaldehyde may be added in amountsof 0.001% to %5, or particularly 0.01% to 1%, or more particularly 0.05%to 0.5%. One particular formulation comprises 0.4% DHE, 0.16% IEacetate, and 0.04% EV, and optimally 0.1% cinnamaldehyde.

Topical cosmetic forms and topical pharmaceutical dosing forms caninclude lotions, shampoos, soaks, gels, creams, ointments and pastes.Lotions commonly employ a water or alcohol base. Gels are semi-solidemulsions or suspensions. Creams generally contain a significantproportion of water in their base while ointments are commonly moreoily.

Liquid forms, such as lotions suitable for topical administration or forcosmetic application, may include a suitable aqueous or non-aqueousvehicle with buffers, suspending and dispensing agents, thickeners,penetration enhancers, and the like. More solid forms such as creams orpastes or the like may include, for example, any of the followingingredients: water, oil, alcohol or grease as a substrate withsurfactant, polymers such as polyethylene glycol, thickeners, solids andthe like. Liquid or solid formulations may include enhanced deliverytechnologies such as liposomes, microsomes, microsponges and the like.

The above-described components for liquid, semisolid and solid topicalcompositions are merely representative. Other materials as well asprocessing techniques and the like are set forth in Remington'sPharmaceutical Sciences, cited above, which is hereby expresslyincorporated herein by reference in its entirety.

When pharmaceutical compositions are to be administered transdermally,they typically are employed as liquid solutions or as gels. In thesesettings, the concentration of DHE and/or IE and or EV and/or salts,esters, ethers, or derivatives thereof ranges, individually or incombination, from about 0.1% to about 20%, such as from about 0.1% toabout 10%, or from 1% to 5%, of the composition with the remainder beingaqueous mixed or nonaqueous vehicle, such as alcohols and the like,suspending agents, gelling agents, surfactant, and the like. Examples ofsuitable such materials are described below.

The compositions comprising DHE and/or IE and/or EV or salts, esters,ethers, or derivatives thereof as defined herein can also beadministered in sustained release transdermal forms or from transdermalsustained release drug delivery systems. A description of representativesustained release materials can be found in the incorporated materialsin Remington's Pharmaceutical Sciences, cited above.

The compositions for systemic administration include compositions fororal administration, that is liquids and solids, and liquid compositionsor suspensions for injection and formulations for rectal, colonic,vaginal, nasal, and parenteral administration.

Compositions for oral administration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical occupant. Typical unit dosage forms includeprofiled, premeasured ampules or syringes of the liquid compositions orpills, tablets, capsules or the like in the case of solid compositions.In such compositions, the DHE and/or IE and/or EV and/or salts, esters,ethers, or derivatives thereof alone or in combination is usually aminor component (from about 0.01 to about 20% by weight or from about0.1 to about 10% by weight or 1% to 5% by weight), with the remainderbeing various vehicles or carriers and processing aids helpful forforming the desired dosing form.

Liquid forms suitable for oral administration may include, but are notlimited to, a suitable aqueous or non-aqueous vehicle with buffers,suspending and dispensing agents, colorants, flavors and the like. Solidforms may include, but are not limited to, any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an occupant suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel™, or corn starch; a lubricant such as magnesium stearate; aglidant such as colloidal silicon dioxide; a sweetening agent such assucrose or saccharin; or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the DHE and/or IE and/or EV and/or salts, esters,ethers, or derivatives thereof in such compositions are typically minorcomponents, often being from about 0.005 to 10% by weight, or 0.1 to 2%by weight, for example, with the remainder being the injectable carrierand the like.

The above-described compositions for orally or epidermally administrableor injectable compositions are merely representative. Other materials aswell as processing techniques and the like are set forth in the part ofRemington's Pharmaceutical Sciences, cited above.

The following formulation examples illustrate representative cosmeticand pharmaceutical compositions of this presently claimed and disclosedinventive concept(s). The presently claimed and disclosed inventiveconcept(s), however, is not limited to the following pharmaceuticalcompositions.

Exemplary Formulations Formulation 1 Lotion

In a particular embodiment, DHE was formulated into a topical lotion a2% final concentration and tested for its ability to block aUVB-irradiation induced sunburn. Volunteers were irradiated with a UVBradiation source sufficient to produce a sunburn (approximately a 3 MEDdose) and after irradiation 1 ml of a 2% topical DHE lotion was appliedto one of two sites. Another irradiated site was left untreated. By 2-6hours erythema was noted in the untreated UVB site while the sidetreated with the topical DHE lotion showed no erythema.

Formulation 2 Liquid

A formulation of DHE (125 mg total), and xanthan gum (4 mg) are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in a water/isopropanol (75:25)mixture. Sufficient water/isopropanol and salicylic acid to 2% by weightor a sufficient amount to maintain a pH of 3-6.5 are then added toproduce a total volume of 5 mL.

Formulation 3 Cream

A commercial mineral oil-water cold cream base is obtained. To 100 gramsof this base, 1 gm of DHE and/or IE and/or EV and/or salts, esters orderivatives thereof as a fine powder or liquid, is added with continuousmixing and stirring to suspend the powder in the base yielding acosmetic or pharmaceutical composition.

In one embodiment, this composition includes the following: deionizedwater (55.6% by weight); niacinamide (2.0%); glycerin (4.0%); phenonip(1.0%); propylene glycol (5.0%); transcutol (3.2%); jojoba Oil (3.5%);isocetyl alcohol (2.0%); isocetyl stearate (3.5%); mineral oil (3.0%);dihydroeugenol (1.0%); salicylic acid (2%); isostearyl palmitate (3.0%);PEG-7 glyceryl cocoate (2.0%); Glycereth-7 (2.0%); POLYSORBATE-20®(0.2%); cetyl ricinoleate (1.0%); glyceryl stearate/PEG-100 stearate(4.0%); and SEPIGEL® (2.0%).

Formulation 4 Cream

Deionized water (56.4% by weight); caffeine (1.0%); butanediol (4.0%);glycerin (1.0%); phenonip (1.0%); POLYSORBATE-20® (0.2%); niacinamide(2.0%); arlacel (6.0%); isocetyl stearate (3.5%); cetyl ricinoleate(1.0%); protaderm B (10.0%); jojoba oil (3.5%); stearyl alcohol (3.0%);cetearyth 20 (0.4%); PEG-12 (3.0%); dihydroeugenol (2.0%); SEPIGEL™(2.0%).

Formulation 5 Cream

Water (44.4% by weight); niacinamide (2.0%); propylene glycol (3%);PEG-100 stearate (1%); ajidew (1%); glycerin (1%); EDTA (0.1%); carbopol(20%); squalene (2%); jojoba oil (2%); stearic acid (2%); glycerylstearate (1%); cetyl alcohol (1.5%); vitamin E (1%); dimethicone (1%);caprylic/capric triglyceride (2%); dihydroeugenol (2%); petrolatum (1%);promulgen D (2%); PP2 (2%); glycol stearate (1%); dimethylisosorbide-DMI (3%); and added after emulsion: germaben (1%)<55°; andtriethanolamine (1%).

Formulation 6 Tablets

A formulation of DHE and/or IE and/or EV and/or salts, esters orderivatives thereof and salicylic acid to maintain a pH of 3-6.5 ismixed with dry gelatin binder and starch diluent in a 0.1:1:1 weightratio. A lubricating amount of magnesium stearate is added and themixture is tabletted into 210 mg tablets containing 10 mg of DHE, IE orEV or other compounds described herein.

Formulation 7 Injection

A formulation of DHE and/or IE and/or salts, esters or derivativesthereof, and salicylic acid to maintain a pH of 3-6.5, is dissolved ininjectable aqueous saline medium at a concentration of 1 mg/ml.

Ethyl Vanillin (EV) Formulations Topical

The following are five non-aqueous formulations comprising EV whichmaintain EV in a chemically-stable condition.

-   -   1. Cyclomethicone (and) dimethiconol (20-90%), caprylic/capric        triglyceride (1-20%), dimethicone (1-10%), ethyl vanillin        (0.1-5%).    -   2. Cyclomethicone (and) dimethiconal (5-60%), cylcopentasiloxane        (and) dimethicone crosspolymer (5-60%), caprylic/capric        triglyceride (1-20%), dimethicone (1-10%), jojoba oil (1-10%),        squalane (1-10%), ethyl vanillin (0.1-5%).    -   3. SD alcohol (5-50%), cetearyl octanoate (1-10%), vitamin E        (0.5%), cyclomethicone (10-50%), PPG-26 oleate (1-10%),        caprylic/capric triglyceride (1-10%), ethyl vanillin (0.1-5%).    -   4. PPG-15 Stearylether cyclomethicone (10-50%), Sunflower oil        (10-50%), isopropyl alcohol (1-10%), isostearyl palmitate        (1-10%), ethyl vanillin (0.1-5%).    -   5. Benzyl laurate (5-25%), PPG-10 butanediol (1-10%), mineral        oil (10-70%), squalane (1-10%), caprylic/capric triglyceride        (1-10%), ethyl vanillin (0.1-5%).

Utility and Dosing

The composition and methods of this presently claimed and disclosedinventive concept(s) can be used topically to treat dermatologicalconditions such as actinic keratitis, acne, scarring, allergic contactdermatitis, atopic dermatitis, contact dermatitis, erythema (sunburn),hand eczema, itch, irritant contact dermatitis, psoriasis, seborrheiceczema (dermatitis), other eczemas, rosacea, hyperpigmentation, alopeciagreata, damage from radiation (radiation dermatitis) including UVradiation, IR radiation and any other ionizing radiation and the like,and other dermatological conditions described elsewhere herein.

The compositions, both cosmetic and pharmaceutical, can also be used totreat and inhibit sunburn and to treat and prevent other forms ofUV-induced inflammation and damage as well as damage from other forms ofionizing radiation.

In these applications the cosmetic and pharmaceutical compositions areadministered topically to achieve a desired cosmetic effect or a topicaltherapeutic effect.

In these uses the dose levels or application levels can be expressed interms of the amount of DHE and/or IE and/or EV and/or salts, esters,ethers, or derivatives thereof delivered to the skin. For example, 1 toabout 5 doses or applications per day, each containing from about 0.001g to about 1 gram of each of DHE and/or IE and/or EV or salts, esters,ethers, or derivatives thereof or combinations thereof can be used.

Alternatively, dose levels can be expressed in terms of the volume offormulated composition administered. For example, 1 to about 5 doses orapplications per day, each containing from about 1 to about 30 grams ofcomposition containing alone or in combination from about 0.01% to about10% by weight of each of DHE and/or IE and/or EV and/or salts, esters,ethers, or derivatives thereof and especially from 0.02% to about 8% byweight or 0.1% to 5% by weight, or 1.0 to 4% by weight.

When used in sun care products, such as suncare lotion, theconcentration of DHE and/or IE and/or EV or salts, esters, ethers, orderivatives thereof can be as set forth above and the product can beapplied as needed based on the intensity and duration of sun exposurebefore, during, or after sun exposure.

Additionally, since the DHE and/or IE and/or EV or salts, esters,ethers, or derivatives thereof have been discovered to effectivelyinhibit the release of cytokines, such a IL-1α or others cited herein,such compounds are useful for treating diseases characterized by anoverproduction or a dysregulated production of cytokines, particularlyIL-1α wherein treatment causes reduction of said cytokines. Elevatedlevels of IL-1α and other cytokines, as noted above, are associated witha wide variety of inflammatory conditions, including rheumatoidarthritis, septic shock, erythema nodosum leprosy, septicemia, adultrespiratory distress syndrome (ARDS), inflammatory bowel disease (IBD),uveitis, damage from ionizing radiation and the like.

In the case of transdermal administration to treat such inflammatoryconditions, one can administer a quantity of composition of thepresently claimed and disclosed inventive concept(s) to a surface areaof skin suitable to achieve an effective systemic bloodstreamconcentration of DHE and/or IE and/or EV, or salts, esters, ethers, orderivatives thereof, e.g., of from about 0.5 μM to about 1000 μM or fromabout 1 μM to about 500 μM, or other concentrations noted herein. Informulations to be applied topically or systemically, it may bepreferred that the skin layer (epidermis and/or dermis) to be affectedby the active agent maintain a concentration of active agent therein ina range of from 1 μM to 1000 μM, such as from 10 μM to 500 μM, or from50 μM to 300 μM, or between 100 μM to 200 μM.

Injection dose levels for treating inflammatory conditions can rangefrom (but are not limited to) about 0.01 mg/kg/hour to at least 1mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from, for example, about 0.01 mg/kg toabout 1 mg/kg or more may also be administered to achieve adequatesteady state levels.

With oral dosing, one to five, two to four, or typically three oraldoses per day are representative regimens. Using these dosing patterns,each dose may provide from about 0.01 to about 10 mg/kg of the DHEand/or IE and/or EV or salts, esters, ethers, or derivatives thereof,with particular doses each providing from about 0.01 to about 5 mg/kg,or other dosages described herein.

The DHE and/or IE and/or EV or salts, esters, ethers, or derivativesthereof can be administered as the sole active agent or they can beadministered alone or in combination, or in combination with otheractive agents.

Although the presently claimed and disclosed inventive concept(s) andits advantages have been described in detail with reference to certainexemplary embodiments and implementations thereof, it should beunderstood that various changes, substitutions, alterations,modifications, and enhancements can be made to the presently claimed anddisclosed inventive concept(s) described herein without departing fromthe spirit and scope of the presently claimed and disclosed inventiveconcept(s) as defined by the appended claims. Moreover, the scope of thepresently claimed and disclosed inventive concept(s) is not intended tobe limited to the particular embodiments of the process, compositions ofmatter, means, methods and steps described in the specification. As oneof ordinary skill in the art will readily appreciate from the disclosureof the presently claimed and disclosed inventive concept(s) manyequivalent processes, compositions of matter, means, methods, or steps,presently existing or later to be developed that perform substantiallythe same function or achieve substantially the same result as thecorresponding embodiments described herein may be utilized according tothe presently claimed and disclosed inventive concept(s) disclosedherein. Accordingly, the appended claims are intended to include withintheir scope all such equivalent processes, compositions of matter,means, methods, or steps.

What is claimed is:
 1. A transdermal composition, comprising: aneffective dermatological disease-treating or dermatologicalcondition-treating amount of an active agent comprising dihydroeugenoland/or a salt thereof and/or an ester thereof; and apharmaceutically-acceptable carrier or vehicle effective in carrying orenabling passage of the active agent into the epidermis or dermis of theskin of the subject where the active agent has its effect on thedermatological disease or dermatological condition.
 2. The transdermalcomposition of claim 1, wherein the dermatological disease ordermatological condition is selected from the group consisting ofinflammation, rosacea, allergic contact dermatitis, irritant contactdermatitis, seborrheic dermatitis, radiation dermatitis, erythema,psoriasis, atopic dermatitis, eczemas, actinic keratitis, acne,scarring, aging, and alopecia greata.
 3. The transdermal composition ofclaim 1, wherein the active agent comprises dihydroeugenol.
 4. Thetransdermal composition of claim 1, wherein thepharmaceutically-acceptable carrier or vehicle comprises a penetrationenhancer.
 5. The transdermal composition of claim 1, wherein thepharmaceutically-acceptable carrier or vehicle comprises a silicone. 6.The transdermal composition of claim 1, further comprisingcinnamaldehyde.
 7. The transdermal composition of claim 1, furthercomprising salicylic acid.
 8. The transdermal composition of claim 1,further defined as being effective in percutaneous transmission suchthat the active agent can be maintained in the epidermis or dermis at aconcentration in a range of from 1 μM to 1000 μM.
 9. A transdermalcomposition, comprising: an effective dermatological disease-treating ordermatological condition-treating amount of an active agent comprising:(1) dihydroeugenol and/or a salt thereof and/or an ester thereof; and(2) isoeugenol and/or a salt thereof and/or an ester thereof; and apharmaceutically-acceptable carrier or vehicle effective in carrying orenabling passage of the active agent into the epidermis or dermis of theskin of the subject where the active agent has its effect on thedermatological disease or dermatological condition.
 10. The transdermalcomposition of claim 9, wherein the dermatological disease ordermatological condition is selected from the group consisting ofinflammation, rosacea, allergic contact dermatitis, irritant contactdermatitis, seborrheic dermatitis, radiation dermatitis, erythema,psoriasis, atopic dermatitis, eczemas, actinic keratitis, acne,hyperpigmentation, scarring, aging, and alopecia greata.
 11. Thetransdermal composition of claim 9, wherein the active agent comprisesdihydroeugenol and isoeugenyl acetate.
 12. The transdermal compositionof claim 9, further comprising soluble ethyl vanillin and/or a saltthereof and/or an ester thereof.
 13. The transdermal composition ofclaim 9, wherein the pharmaceutically-acceptable carrier or vehiclecomprises a penetration enhancer.
 14. The transdermal composition ofclaim 9, wherein the pharmaceutically-acceptable carrier or vehiclecomprises a silicone.
 15. The transdermal composition of claim 9,further comprising cinnamaldehyde.
 16. The transdermal composition ofclaim 9, further comprising salicylic acid.
 17. The transdermalcomposition of claim 9, further defined as being effective inpercutaneous transmission such that the active agent can be maintainedin the epidermis or dermis at a concentration in a range of from 1 μM to1000 μM.
 18. A transdermal composition, comprising: an effectivedermatological disease-treating or dermatological condition-treatingamount of an active agent comprising: (1) dihydroeugenol and/or a saltthereof and/or an ester thereof; and (2) soluble ethyl vanillin and/or asalt thereof and/or an ester thereof; and a pharmaceutically-acceptablecarrier or vehicle effective in carrying or enabling passage of theactive agent into the epidermis or dermis of the skin of the subjectwhere the active agent has its effect on the dermatological disease ordermatological condition.
 19. The transdermal composition of claim 18,wherein the dermatological disease or dermatological condition isselected from the group consisting of inflammation, rosacea, allergiccontact dermatitis, irritant contact dermatitis, seborrheic dermatitis,radiation dermatitis, erythema, psoriasis, atopic dermatitis, eczemas,actinic keratitis, acne, scarring, aging, and alopecia greata.
 20. Thetransdermal composition of claim 18, wherein thepharmaceutically-acceptable carrier or vehicle comprises a penetrationenhancer.
 21. The transdermal composition of claim 18, wherein thepharmaceutically-acceptable carrier or vehicle comprises a silicone. 22.The transdermal composition of claim 18, further comprisingcinnamaldehyde.
 23. The transdermal composition of claim 18, furthercomprising salicylic acid.
 24. The transdermal composition of claim 18,further defined as being effective in percutaneous transmission suchthat the active agent can be maintained in the epidermis or dermis at aconcentration in a range of from 1 μM to 1000 μM.
 25. A transdermalcomposition, comprising: an effective dermatological disease-treating ordermatological condition-treating amount of an active agent comprisingisoeugenol acetate; and a pharmaceutically-acceptable carrier or vehicleeffective in carrying or enabling passage of the active agent into theepidermis or dermis of the skin of the subject where the active agenthas its effect on the dermatological disease or dermatologicalcondition.
 26. The transdermal composition of claim 25, wherein thedermatological disease or dermatological condition is selected from thegroup consisting of inflammation, rosacea, allergic contact dermatitis,irritant contact dermatitis, seborrheic dermatitis, radiationdermatitis, erythema, psoriasis, atopic dermatitis, eczemas, actinickeratitis, acne, hyperpigmentation, scarring, aging, and alopeciagreata.
 27. The transdermal composition of claim 25, further comprisingethyl vanillin and/or a salt thereof and/or an ester thereof.
 28. Thetransdermal composition of claim 25, wherein thepharmaceutically-acceptable carrier or vehicle comprises a penetrationenhancer.
 29. The transdermal composition of claim 25, wherein thepharmaceutically-acceptable carrier or vehicle comprises a silicone. 30.The transdermal composition of claim 25, further comprisingcinnamaldehyde.
 31. The transdermal composition of claim 25, furthercomprising salicylic acid.
 32. The transdermal composition of claim 25,further defined as being effective in percutaneous transmission suchthat the active agent can be maintained in the epidermis or dermis at aconcentration in a range of from 10 μM to 500 μM.